3 and 5 alkyl and phenyl 4-(hydroxy or acyloxy)-alkyl substituted 2(5H)-furanones as anti-inflammatory agents

ABSTRACT

Novel anti-inflammatory furanone compounds have the following formula: ##STR1## where R 1  independently is H, or alkyl of 1 to 9 carbons and n is an integer having the values of 1 or 2, and where when n is 1 the R 1  group is attached to the 5 position of the 2-furanone, when n is 2 then R 1  is attached to both the 3 and 5 positions, with the proviso that when n is 1 then R 1  is not H; Y 1  is H, alkyl of 1 to 20 carbons, phenyl C 1  -C 20  alkyl, C 1  -C 20  alkenyl containing one or more olefinic bonds, where R 3  is H, C 1  -C 20  alkyl, C 1  -C 20  alkenyl containing one or more olefinic bonds, phenyl, halogen substituted phenyl or C 1  -C 6  alkyl substituted phenyl, with the proviso that when Y 1  is CO--OR 3  or CONHR 3  then R 3  is not hydrogen; Y 2  is H, an alkyl group of 1 to 25 carbons, or phenyl.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to novel 2- and 5-alkyl and phenylsubstituted 4-(1-hydroxy-, 1-acyloxy-, or1-carbamoyloxy)-2(5H)-furanones which compounds are active asanti-inflammatory agents. The present invention is also directed topharmaceutical compositions which comprise one or more of the novelcompounds of the invention, to the methods of using these pharmaceuticalcompositions, and to the chemical processes of making the novelcompounds.

2. Brief Description of the Prior Art

Manoalide is a compound isolated from a marine sponge [E. D. de Silva etal., Tetrahedron Letters 21:1611-1614 (1980)] which hasanti-inflammatory, immunosuppressive and analgesic properties. Manoalidethe structure of which is shown below, includes a5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of thefuranone ring to the rest of the molecule. Certain analogs of manoalide,such as seco-manoalide and dehydro-seco-manoalide also haveanti-inflammatory activity. For further description of the biologicalactivity of manoalide and some of its derivatives reference is made toU.S. Pat. Nos. 4,447,445, 4,786,651, 4,789,749 and to European PatentApplication No. 0 133 376 (published on Feb. 20, 1985). ##STR2##

Synthetic analogs of manoalide, particularly analogs having varioussubstituents on the furanone moiety of manoalide, are described inseveral United States patents and applications for United States patentassigned to the same assignee as the present application. Among these,U.S. Pat. No. 5,045,564 discloses 4-substituted 2-5(H)-furanones asanti-inflammatory and calcium channel antagonist agents. U.S. Pat. No.5,183,906 (issued on Feb. 2, 1993) 3 and 5 alkyl and phenyl4-(1-hydroxy, 1-acyloxy or 1-carbamoyloxy)-5-hydroxy-2-furanones, asanti-inflammatory and calcium channel antagonist agents.

U.S. Pat. No. 5,268,387 describes a method for treating an imbalancebetween bone production and resorption with furanone compounds, thegeneral examples of which include 3 and 5 alkyl and phenyl 4-(1-hydroxy,1-acyloxy or 1-carbamoyloxy)-2-furanones, and the specific examples ofwhich include 3 and 5 alkyl and phenyl 4-(1-hydroxy, 1-acyloxy or1-carbamoyloxy)-5-hydroxy-2-furanones.

European Patent Application No. 0 534 907 A1 (published Mar. 31, 1993)discloses 3,5-dialkyl, 3,5,-dialkyl-4-hydroxy, and3,4,5-trialkyl-2-furanones as agents for treatment of autoimmunediseases.

As further general background Published European Patent Application No.0 295 056 is noted, which discloses 4-substituted5-hydroxy-2(5H)-furanones having anti-inflammatory, immunosuppressiveand anti-proliferative activity where the substituents in the 4 positionare a variety 1-hydroxyalkyl, 1-acyloxy-alkyl and 1-carbamoyloxy-alkylgroups.

U.S. Pat. No. 4,855,320 discloses 5-arylalkyl-4-alkoxy-2(5H)-furanonesas anti-convulsive and anti-epileptic agents.

Published European Patent Application No. 0 209 274 discloses4-alkyl-5-hydroxy-2(5H)-furanones as anti-inflammatory and anti-allergyagents.

Chemical Abstracts Volume 107 236559t (1987) discloses 4-acyloxy5-hydroxy-2(5H)-furanones.

2-Substituted 4-furaldehydes (5-substituted 3-furaldehydes) aredescribed in U.S. Pat. No. 4,935,530.

SUMMARY OF THE INVENTION

The present invention covers compounds of Formula ##STR3## where R₁independently is H, phenyl, C₁ -C₆ alkyl substituted phenyl, halogensubstituted phenyl, or alkyl of 1 to 9 carbons and n is an integerhaving the values of 1 or 2, and where when n is 1 the R₁ group isattached either to the 3 or to the 5 position of the 2-furanone, when nis 2 then R₁ is attached to both the 3 and 5 positions, with the provisothat the substituents in the 3 and 5 positions both cannot be hydrogen;

Y₁ is H, alkyl of 1 to 20 carbons, phenyl C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olefinic bonds, PO(OH)₂, PO(OH)OR₂, PO(OH)R₂,PO(OR₂)₂, where R₂ is independently alkyl of 1 to 20 carbons, phenyl,halogen substituted phenyl or C₁ -C₆ alkyl substituted phenyl, furtherY₁ is CO--R₃, CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃, (CH₂)_(p) --O--R₃, or(CH₂)_(p) --O--(CH₂)_(m) --O--R₃, where p, and m, are integers and areindependently 1 to 20 and R₃ is H, C₁ -C₂₀ alkyl, C₁ -C₂₀ alkenylcontaining one or more olefinic bonds, phenyl, halogen substitutedphenyl or C₁ -C₆ alkyl substituted phenyl, with the proviso that when Y₁is CO--OR₃ or CONHR₃ then R₃ is not hydrogen;

Y₂ is H, an alkyl group of 1 to 25 carbons, phenyl, naphthyl, phenyl (C₁-C₂₀)alkyl-, naphthyl (C₁ -C₂₀)alkyl-, halogen substituted phenyl, C₁-C₆ alkyl substituted phenyl, halogen substituted naphthyl, C₁ -C₆substituted naphthyl.

The present invention also covers salts of the above-defined compounds,formed with pharmaceutically acceptable acids or bases, as applicable.

In a second aspect the present invention relates to pharmaceuticalformulations comprising one or more compounds of Formula 1 (orpharmaceutically acceptable salts thereof) in admixture with apharmaceutically acceptable excipient, for the purpose of treatingcertain conditions, syndromes or diseases in mammals, including humans.The compounds of the invention have anti-inflammatory, immunosuppressantand anti-proliferative activity without having significant contactsensitizing activity on the mammalian skin. Therefore, the compounds areuseful for treating in mammals (including humans) inflammation,rheumatoid arthritis, osteoarthritis, rheumatic carditis, ocular anddermal inflammatory diseases, autoimmune diseases such as allergicdiseases, bronchial asthma and myasthenia gravis, and for suppressingunwanted immune responses and retarding proliferation of cell.

In still another aspect, the present invention relates to the processesof making the compounds of Formula 1. In general terms, these processes,shown in a summarized fashion in Reaction Scheme 1 comprise the step ofreducing a compound of Formula 2 to provide a compound of Formula 1. Asthe reaction scheme shows, this reduction results in the replacement ofthe 5-hydroxy function of the 2-furanone moiety with a hydrogen group,thereby providing a "5-deshydroxy" compound. Generally speaking, thecompounds of Formula 2 are obtained in accordance with the teachings andsynthetic procedures described in U.S. Pat. No. 5,183,906 thespecification of which is hereby expressly incorporated by reference.Compounds of Formula 1 where the Y₁ group is other than hydrogen canalso be obtained by introducing the Y₁ substituent into thecorresponding hydroxy compound (where Y₁ is hydrogen) by alkylation,acylation reaction with an isocyanate, or other reaction known in theart and appropriate to introduce the Y₁ group into an alcohol such asthe Y₂ CH(OH)-moiety of the substituted furanones of this invention.##STR4##

General Embodiments

Definitions

The terms "ester", "amine", "amide", "ether" and all other terms andterminology used here, (unless specifically defined in the presentdescription) refer to and cover any compounds falling within therespective term as that term is classically used in organic chemistry.

Unless specifically noted otherwise, preferred esters are derived fromthe saturated aliphatic alcohols or acids of ten or fewer carbon atomsor from the cyclic or saturated aliphatic cyclic alcohols and acids of 5to 10 carbon atoms. Particularly preferred aliphatic esters are thosederived from lower alkyl acids or alcohols. Also preferred are thephenyl or lower alkylphenyl esters.

The term "alkyl" as used in the present description and claims includesstraight chain alkyl groups, branched chain alkyl groups, cycloalkylgroups, alkyl substituted cycloalkyl groups, and cycloalkyl substitutedalkyl groups. Unless the number of carbons is otherwise specified,"lower alkyl" means the former broad definition of "alkyl" groups butwith the restriction that the group has 1 to 6 carbon atoms.

Unless specifically noted otherwise, the term "long chain alkyl" alsomeans the former broad definition of "alkyl" groups but with therestriction that the group has no less than 4 carbon atoms, and no morethan approximately 25 carbon atoms.

Unless specifically noted otherwise, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms, or the cyclic or saturated aliphaticcyclicradicals of 5 to 10 carbon atoms.

Certain compounds of the invention contain a chiral center at the alphacarbon in the side chain on the 4-position of the 2(5H)-furanone moiety.Other compounds of the invention may contain more than one chiralcenter. Accordingly, the compounds of the invention may be prepared asmixtures of enantiomeric compounds (where the enantiomers may or may notbe present in equal amounts) or as optically pure enantiomers. Whenthere is more than one chiral center, the compounds of the invention mayalso be prepared as mixtures of diastereomers, or as pure diastereomers,and each diastereomer itself may be a mixture of enantiomers in 1:1, orother, ratios. Alternatively, each diastereomeric compound may besterically and optically pure. However, all of the above-noted forms,including optically pure enantiomers and mixtures thereof, as well asall diastereomers, are within scope of the present invention.

Some of the compounds of the invention may have cis and transstereoisomers. The scope of the invention includes both purestereoisomers as well as mixtures thereof.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The preferred compounds of the present invention, with reference toFormula 1 and with respect to the R₁ substituent are those where R₁ isalkyl, more preferably alkyl of 1 to 6 carbons, and stil more morepreferably methyl. Also preferred are the compounds where R₁ is phenyl.

Regarding the Y₁ substituent, compounds are preferred in accordance withthe present invention where the Y₁ is H, or an acyl group, designatedCO--R₃ in Formula 1. More preferably, the acyl group is acetoxy, or along chain lipophilic acyl group where the R₃ group is long chain alkyl.Especially preferred are compounds where the acyl group is lauroyl.

Regarding the Y₂ substitutent, compounds are preferred in accordancewith the present invention where Y₂ is long chain alkyl, preferablyalkyl having 8 to 16 carbons, even more preferably alkyl having 12carbons. Compounds are also preferred in accordance with the presentinvention where Y₂ is hydrogen, provided the Y₁ group is then a longchain lipophilic acyl group. The most preferred compounds of theinvention are listed below with reference to Formula 1:

Compound 1: n=1, R₁ =5-methyl, Y₁ =CH₃ CO; Y₂ =(CH₂)₁₁ --CH₃

Compound 2: n=1, R₁ =3-methyl, Y₁ =CH₃ CO; Y₂ =(CH₂)₁₁ --CH₃

Compound 3: n=1, R₁ =5-methyl, Y₁ =H; Y₂ =(CH₂)₁₁ --CH₃

Compound 4: n=2, R₁ =3-phenyl, R₁ =5-methyl Y₁ =CO(CH₂)₁₀ CH₃, Y₂ =H

The compounds of the present invention are useful in pharmaceuticalcompositions to produce anti-inflammatory, immunosuppressant andanti-proliferative activity. The diseases, syndromes or conditions ofmammals (including humans) which can be treated with pharmaceuticalcompositions containing one or more compounds of the invention (or saltsthereof) include: inflammation, rheumatoid arthritis, osteoarthritis,rheumatic carditis, ocular and dermal inflammatory diseases, autoimmunediseases such as allergic diseases, bronchial asthma and myastheniagravis, unwanted immune responses and unwanted proliferation of cells,psoriasis, acne, atopic diseases and allergic conjunctivitis.

The compounds of this invention are tested as inhibitors of the enzymephospholipase A₂ in vitro, and for reduction of inflammation in themouse ear anti-inflammatory assay in vivo.

The compounds of the invention modify calcium homeostasis. This activityis shown by effect on intracellular calcium levels in experiments usinggastric glands, spleen cells, epithelial cells, GH₃ cells, etc. Calciumis inhibited from entering through the plasma membrane calcium channelsand calcium release from intracellular stores is also blocked.Modification of calcium homeostasis is expected to have application indiseases of the nervous system involving modification of membrane lipidsor transmitter release (Parkinson's, Alzheimer's), diseases of thecardiovascular system involving application of cardiac or vascularsmooth muscle contractility and platelet aggregation (hypertension,cardiac infarction and atherosclerosis), diseases of thegastrointestinal tract such as ulcer disease, diarrhea, motility due tosecretion of acid or C1⁻, diseases of the kidney involving renalhandling of fluid and electrolytes (metabolic acidosis, alkalosis), anddisease of abnormal growth (neoplasia, psoriasis).

The compounds of this invention have activity which is similar to thatof manoalide, that is the compounds appear to be devoid of the endocrineproperties of the glucocorticoids while having anti-inflammatory andimmunosuppressive properties. In addition those compounds of theinvention which have a substituent in the 5 position lack certaindisadvantageous skin-sensitizing properties of certain5-hydroxy-2(5H)-furanone derivatives which otherwise haveanti-inflammatory activity. Still further, as the data below indicatethe compounds of the invention are essentially inactive in thephospholipase A₂ assay, but active in the Ca⁺⁺ channel inhibition assay.Thus, the compounds are selective inhibitors of the Ca⁺⁺ channel. While,generally speaking activity, in either the phospholipase A₂ or in theCa⁺⁺ channel assay are hallmarks of anti-inflammatory activity,selectivity for Ca⁺⁺ channel inhibition is also a highly desirablepharmacological property. The Ca⁺⁺ channel selectivity of the compoundsof the present invention is unusual and certainly surprising in light ofthe known prior art.

In the methods of this invention, the compounds of the invention areadministered to mammals, including humans, in an effective amount toproduce the desired activity, preferably in an amount of about 0.05 to100 mg per day per kilogram of body weight. The amount of the compounddepends upon the disease or condition being treated, the severitythereof, the route of administration and the nature of the host. Thecompounds may be administered topically, orally, parenterally or byother standard routes of administration.

Pharmaceutical compositions of this invention comprise compounds ofFormula 1, and pharmaceutical carriers suitable for the route ofadministration. Standard methods for formulating pharmaceuticalcompositions of this type may be found in Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa.

For topical administration, the pharmaceutical composition may be in theform of a salve, cream, ointment, spray, powder or the like. Standardpharmaceutical carriers for such compositions may be used. Preferably,compositions for topical administration will contain 0.05-5% of theactive ingredient.

A typical cream formulation may contain the following:

    ______________________________________                                        Ingredient          Parts by Weight                                           ______________________________________                                        Water/glycol mixture                                                                              50-99                                                     (15% or more glycol)                                                          Fatty alcohol       1-20                                                      Non-ionic surfactant                                                                              0-10                                                      Mineral oil         0-10                                                      Typical pharmaceutical adjuvants                                                                  0-5                                                       Active ingredient   0.05-5                                                    ______________________________________                                    

A typical ointment formulation may contain the following:

    ______________________________________                                        Ingredients     Parts by Weight                                               ______________________________________                                        White petrolatum                                                                              40-94                                                         Mineral oil     5-20                                                          Glycol solvent  1-15                                                          Surfactant      0-10                                                          Stabilizer      0-10                                                          Active ingredient                                                                             0.05-5                                                        ______________________________________                                    

For oral administration, suitable pharmaceutical carriers includemannitol, lactose, starch, magnesium stearate, talcum, glucose andmagnesium carbonate. Oral compositions may be in the form of tablets,capsules, powders, solutions, suspensions, sustained releaseformulations, and the like.

A typical tablet or capsule may contain the following:

    ______________________________________                                        Ingredients      Percent w/w                                                  ______________________________________                                        Lactose, spray-dried                                                                           40-99                                                        Magnesium stearate                                                                             1-2                                                          Cornstarch       10-20                                                        Active ingredient                                                                              0.001-20                                                     ______________________________________                                    

Parenteral compositions are prepared in conventional suspension orsolution forms, as emulsions or as solid forms for reconstruction.Suitable carriers are water, saline, dextrose, Hank's solution, Ringer'ssolution, glycerol, and the like. Parenteral administration is usuallyby injection which may be subcutaneous, intramuscular or intravenous.

The compounds of this invention may be combined with other knownanti-inflammatory/immunosuppressive agents such as steroids ornon-steroidal anti-inflammatory agents (NSAID) in the pharmaceuticalcompositions and methods described herein.

The assay procedures by which useful biological activity of thecompounds of the invention can be tested and/or demonstrated, aredescribed below.

Calcium Channel (mobilization) Inhibition Assay

Polymorphonuclear leukocytes (PMNa), gastric glands, GH₃ cells, A431cells, spleen cells, human keratinocytes corneal cells, etc. were loadedwith the Ca²⁺ sensitive fluorescent dye, Fura-2. The appropriate celltype was chosen and the potency and efficacy of the anti-inflammatoryfuranones on calcium mobilization, calcium channel inhibition wasquantitated. The methods used for A431 cells listed below arerepresentative of those used for other cells.

A431 cells were detached using a 5-10 min trypsin-EDTA treatment whereasGH₃ cells were treated 2 to 5 min with a 1% pancreatin solution. Cellswere immediately washed twice in a 20 mM HEPES buffer (pH 7.4)containing 120 mM NaCl, 6 mM KCl, 1 mM MgSO₄, 1 mg/ml glucose and 1mg/ml pyruvate and 1.4 mM calcium (medium A). Approximately 5×10⁶ cellswere suspended in medium A and incubated with 4 uM fura-2-AM for 15 minat 37° C.

After washing the fura-2 loaded cells, the uptake of dye was checkedusing fluorescence microscopy and found to be evenly distributed in thecytosol of all cells. Fluorescence was continuously recorded with aPerkin-Elmer LS-5 spectrofluorometer. The excitation wavelength was setat 340 nm and emission wavelength set at 500 nm. The cell suspension wascontinually stirred, maintained at 37° C. and equilibrated forapproximately 5 min before addition of various agents. [Ca²⁺ i wascalculated using the following formula: ##EQU1##

All fluorescence values were measured relative to a EGTA-quenched signaldetermined as follows: F was the relative fluorescence measurement ofthe sample. F_(max) was determined by lysing the cells with digitonin(100 ug/ml) in DMSO. After F_(max) was determined the pH was adjusted to8, with NaOH and Ca²⁺ chelated with 3 mM EGTA to totally quench thefura-2 signal and obtain F_(min).

When quin-2- was used, cells were incubated with 10 uM quin-2- at 37° C.for 1 hour, washed and then used.

Mouse Ear Anti-Inflammatory Assay

Test compound and phorbol myristate acetate (PMA) are topically appliedsimultaneously to the pinnae of the left ears of mice. PA alone isapplied to the right ear. Three hours and 20 minutes after application,the mice are sacrificed, left and right ears removed, and standard sizedbores taken. Edema (inflammation) is measured as the difference inweight between left and right ears [Van Arman, C. G., Clin PharmacolTher (1974) 16:900-904].

Inhibition of Phospholipase A₂

The effect of compounds of this invention on bee venom phospholipase A₂is determined by the following procedure:

a. Bee venom phospholipase A₂ in 10 uM HEPES (pH 7.4) with 1 mM CaCl₂ isincubated with vehicle or test agent for 1.0 hour at 41°.

b.1.36 mM phosphotidylcholine, 2.76 mM Triton X-100 are dispersed inbuffer by sonication and then mixed with L-3 phosphotidylcholine,1-palmitoyl-2-(1-¹⁴ C) palmitoyl for 10 min.

c. Start the reaction by the addition of enzyme (0.495 units/ml).

d. Incubation for 15 sec. at 41°.

e. Reaction is terminated by addition of 2.5 ml of isopropanol:n-heptane: 0.5M H₂ SO₄ (40:10:1; v:v:v:).

f. 2.0 ml n-heptane and 1.0 ml H₂ O added; mixture centrifuged.

2.0 ml n-heptane removed and treated with 200-300 mg of silica gel HR60.

h. Samples centrifuged; 1 ml of n-heptane SN removed and added to 10 mlscintillation fluid.

i. Samples counted on a scintillation counter.

Activity Data

In the above-described phospholipase A₂ assay and Calcium²⁺ channelmobilization assay the compounds of the invention were found to provide50% inhibition (IC₅₀) at the following concentrations (in micromoles),as indicated in Table 1.

                  TABLE 1                                                         ______________________________________                                        Phospholipase A2 Assay.                                                       Compound name or number                                                       (micromolar)         IC.sub.50                                                ______________________________________                                        1                    inactive at 3 μM                                      2                    inactive at 3 μM                                      3                    inactive at 3 μM                                      4                    inactive at 3 μM                                      manoalide            0.03                                                     ______________________________________                                        Calcium.sup.2+  Channel Mobilization Inhibition Assay                                        IC.sub.50 (micromolar)                                         Compound name or number                                                                        TRH induced                                                                              KCl induced                                       ______________________________________                                        1                6.4        0.36                                              2                1.0        0.25                                              3                 0.67      0.47                                              4                inactive   8.0                                               manoalide*       0.6        0.8                                               ______________________________________                                         *Data for manoalide are provided for comparison.                         

SPECIFIC EMBODIMENTS

The compounds of the present invention can be made by the syntheticchemical pathways which are illustrated here in general terms, byreference to U.S. Pat. No. 5,183,906 (the specification of which isexpressly incorporated herein) and in the below given specific examples.The synthetic chemist will readily appreciate that the conditionsdescribed here in general terms, and specifically, can be generalized toany and all compounds represented by Formula 1. Furthermore, thesynthetic chemist will readily appreciate that the herein describedsynthetic steps may be varied or adjusted by those skilled in the artwithout departing from the scope and spirit of the invention.

Generally speaking, the the compounds of the present invention which, inaccordance with Formula 1 lack the 5-hydroxy function on the furannucleus, can be obtained by reducing with sodium borohydride (or with acomparable mild reducing agent) the corresponding 5-hydroxy-2-furanonecompounds. This general reaction is illustrated above in Reaction Scheme1.

The 5-hydroxy 2-furanone compounds of Formula 2 which serve as startingmaterials for the reduction illustrated in Reaction Scheme 1 can beobtained in accordance with the synthetic procedures described in U.S.Pat. No. 5,183,906 ('906 patent).

Specifically, Reaction Scheme 2 and the accompanying pertinentdescription of the '906 patent disclose a synthetic process forpreparing the 5-alkyl or phenyl substituted 5-hydroxy-2-furanonederivatives which can serve as the appropriately substituted startingmaterials of Formula 2 in Reaction Scheme 1 of the present disclosure.

Reaction Scheme 3 and the accompanying pertinent description of the '906patent disclose a synthetic process for preparing the 3-alkylsubstituted 5-hydroxy-2-furanone derivatives which can serve as theappropriate starting materials of Formula 2 in Reaction Scheme 1 of thepresent disclosure.

The starting materials of Formula 2 for the preparation of compounds ofthe present invention which are 3,5-dialkyl-2-furanone derivatives, canbe made in accordance with the description provided in column 13 of thereference '906 patent.

The starting materials of Formula 2 for the preparation of compounds ofthe present invention which are 3-phenyl and 3-phenyl-5-alkyl-2-furanonederivatives, can be made in accordance with Reaction Schemes 4 and 5,respectively, and the attendant description and examples provided in thereference '906 patent.

As is described in the reference '906 patent, preparation of the5-hydroxy-2-furanones starting materials of Formula 2 (of the thisdisclosure) normally includes a step of oxidation with singlet oxygen,which step utilizes Rose Bengal dye as a catalyst and requiresirradiation by light. Generally speaking, the step of singlet oxidationis conducted on a precursor compound of Formula 2 which has a Y₁substituent other than hydrogen, for example an alkyl or an acyl group.The Y₁ group is introduced with an alkylating, acylating,alkylsulfonylating reagent, with an isocyanate or with other appropriatereagent, to the hydroxyl function in the side chain of the 4-position ofthe furan nucleus. As it will become apparent from the ensuing specificexamples, the Y₁ can also be introduced by an alkylating, acylating orother appropriate reagent to the hydroxyl function in the side chain ofthe 4-position on the furan nucleus after singlet oxidation, and afterthe reduction step pursuant to Reaction Scheme 1 has already beenperformed.

The reduction step of Reaction Scheme 1 can, generally speaking, beconducted on compounds of Formula 2 where Y₁ is either hydrogen or analkyl or an acyl group. This reaction is typically conducted in ananhydrous ether-type solvent, such as tetrahydrofuran or ethylene glycoldimethyl ether, under a blanket of inert gas, such as argon, at roomtemparature or at 0° C., typically for 2 or 3 hours. ##STR5##

The compound 4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone(Compound 5) serves as the starting material for the preparation ofCompound 4 of the present invention. The preferred synthetic procedure,illustrated in Reaction Scheme 2, for obtaining this compound involvesthe step of saponifying Compound 5, followed by reduction with sodiumborohydride of the resulting4-hydroxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 6) toyield Compound 7. Compound 7 is then subsequently reesterified bytreatment with lauroyl chloride to yield Compound 4 of the invention.

The starting material4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5)is described in the reference '906 patent (see Column 27, lines 7-30)and can be prepared in accordance with the synthetic procedure disclosedin the reference '906 patent. The presently prefered procedure forobtaining relatively larger quantitities of Compound 5 differs, however,in certain steps and conditions from the procedure disclosed in thereference '906 patent, and is therefore described here in connectionwith Reaction Scheme 3. ##STR6##

In accordance with Reaction Scheme 3, 4-phenyl-3-furylcarbinol (Compound10) is oxidized to yield 4-phenyl-3-furaldehyde (Compound 11), which isthereafter reacted sequentially with lithium morpholide, sec-butyllithium and trimethylsilyl chloride to yield4-phenyl-5-trimethylsilyl-3-furancarboxaldehyde (Compound 12). The firstcompound in this scheme, 4-phenyl-3-furylcarbinol (Compound 10) isdescribed in the reference '906 patent (see column 24) and can beobtained from commercially available starting materials, in accordancewith the procedure described in that patent, and also described here.

4-Phenyl-5-trimethylsilyl-3-furancarboxaldehyde (Compound 12) is reducedwith lithium aluminum hydride to yield the corresponding alcohol(Compound 13), which is thereafter methylated with methyl iodide in thepresence of n butyl lithium and lithium chloride in the 5-position ofthe furan nucleus to yield5-trimethylsilyl-4-phenyl-3-hydroxymethyl-2-methylfuran (Compound 14).5-Trimethylsilyl-4-phenyl-3-hydroxymethyl-2-methylfuran (Compound 14) isesterified by treatment with lauroyl chloride in the presence oftriethylamine to yield5-trimethylsilyl-4-phenyl-3-dodecoyloxymethyl-2-methylfuran (Compound15). Compound 15 is subjected to singlet oxidation, in a chilled(approximately -5° C.) dry tetrahydrofuran solution, in the presence ofRose Bengal dye under irradiation with light to provide4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5).

The following examples of specific compounds of the invention, andspecific examples of the synthetic steps in which the compounds andcertain intermediates are made, are set out to illustrate the invention,not to limit its scope.

SPECIFIC EXAMPLES

4-(1-Acetoxytridecyl)-3-methyl-2-furanone (Compound 2)

NaBH₄ (25 mg, 0.67 mmol) was added to a solution of4-(1-acetoxytridecyl)-3-methyl-5-hydroxy-2(5-H)-furanone (157 mg, 0.44mmol) in anhydrous THF (20 mL) at room temperature under argon. After 2hours aqueous HCL (1N) was added carefully until pH2 was reached and theresulting mixture was stirred an additional 1 hour. This mixture wasextracted with ethyl acetate and the combined organic fractions werewashed with 5% sodium bicarbonate and brine. Evaporation of the dried(magnesium sulfate) extracts gave an oil which was purified by flashchromatography on silica using 30% ethyl acetate/hexane. Fractions withR_(f) of about 0.45 on evaporation afforded the title compound.

IR (CHCl₃): 1753 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.7 Hz, 3H), 1.19-1.38 (m, 20H), 1.58-1.72(m, 1H), 1.73-1.88 (m, 1H), 1.91 (m, 3H), 2.09 (s, 3H), 4.66 (dd, J=17.2Hz, J=2.0 Hz, 1H), 4.77 (dd, J=17.2 Hz, J=2.0 Hz, 1H), 5.69 (t, J=6.9Hz, 1H).

¹³ C NMR (CDCl₃): 8.9, 14.0, 20.6, 22.5, 24.9, 29.0, 29.1, 29.2, 29.3,29.4, 29.5, 31.8, 33.1, 68.9, 69.3, 124.6, 156.7, 169.8, 174.4.

Elemental analysis: theoretical carbon 70.97%, found 70.60%, theoreticalhydrogen 10.12%, found 9.91%.

4-(1-Hydroxytridecyl)-5-hydroxy-5-methyl-2-furanone

LiOH (0.5M, 22.6 mL, 11.32 mmol) was added to a solution of4-(1-acetoxytridecyl)-5-hydroxy-5-methyl-2-furanone (1.00 g, 2.83 mmol)in THF (15 mL). After stirring for 3 hours at room temperature thereaction was quenched with glacial acetic acid (680 mg, 11.3 mmol) andextracted with ethylacetate. The combined organic fractions were washedwith a saturated solution of aqueous sodium bicarbonate, H₂ O and brine.Evaporation of the dried (magnesium sulfate) extracts gave an oil whichwas purified by flash chromatography on silica using 40% ethylacetate/hexane to give the title alcohol.

IR (CHCl₃): 3376 (br), 1761 cm⁻¹ 1 H NMR (CDCl₃), mixture ofdiastereomers: 0.88 (t, J=6.7 Hz, 3H), 1.2-1.6 (m, 20H), 1.65-1.90 (m,5H) , 2.4 (brs, 0.5H), 2.9 (brs, 0.5H), 4.3 (brs, 0.5H), 4.56 (brt,J=5.0 Hz, 1H), 4.8 (brs, 0.5H), 5.96 (S, 1H).

¹³ C NMR (CDCl₃), mixture of diastereomers: 14.1, 22.8, 24.2, 25.3, 29.329.5, 29.6, 31.9, 35.5, 66.7, 66.9, 68.0, 107.2, 107.3, 116.5, 171.2,173.7.

Elemental analysis: theoretical carbon 69.19%, found 69.08%, theoreticalhydrogen 10.33% found 10.60%.

4-(1-Hydroxytridecyl)-5-methyl-2(5H)-furanone (Compound 3)

NaBH₄ (210 mg, 5.54 mmol) was added in portions to a solution of4-(1-hydroxytridecyl)-5-hydroxy-5-methyl-2-furanone (586 mg, 1.85 mmol)in anhydrous ethyle glycol dimethyl ether (60 mL) at 0° C. under argon.After stirring for 3 hours at 0° C. the reaction was quenched with HCl(6N) to pH2 and extracted with ethyl acetate. The combined organicfractions were washed with a saturated solution of aqueous sodiumbicarbonate, H₂ O and brine. Evaporation of the dried (magnesiumsulfate) extracts gave an oil which was purified by flash chromatographyon silica using 30% ethyl acetate/hexane to give the title compound as amixture of diastereomers. Recrystallization from diethyl ether/hexanegave a single diastereomer.

IR (CHCl₃): 1751 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.7 Hz, 3H), 1.2-1.5 (m, 20H), 1.53 (d,J=6.7 Hz, 3H), 1.65 (brs, 1H), 1.66-1.86 (m, 2H), 4.51 (m, 1H), 5.20 (q,J=6.7 Hz, 1H), 5.86 (s, 1H).

¹ H NMR (CDCl₃): 14.1, 18.7, 22.7, 25.1, 29.3, 29.4, 29.5, 29.6, 31.9,35.6, 67.7, 79.8, 115.2, 172.8, 175.3.

Elemental analysis; theoretical carbon 71.83%, found 72.09%, theoreticalhydrogen 10.89%, found 10.91%.

4-(1-Acetoxytridecyl)-5-methyl-2(5H)-furanone (Compound 1)

4-(1-Hydroxytridecyl)-5-methyl-2(5H)-furanone (Compound 3, 329 mg, 1.11mmol), acetic anhydride (453 mg, 4.45 mmol), triethylamine (227 mg, 2.22mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol ) were stirred atroom temperature under argon for 3 hours in anhydrous THF (30 mL). Thecrude reaction mixture was concentrated and the residue was taken up indiethyl ether and washed with a 10% aqueous HCl solution, a saturatedsolution of sodium bicarbonate, H20 and brine. Evaporation of the dried(magnesium sulfate) extracts gave an oil which was purified by flashchromatography on silica using 20% ethyl acetate/hexane to give thetitle compound.

IR (CHCl₃): 1751 cm⁻¹.

¹ H NMR (CDCl₃), mixture of diastereomers: 0.88 (t, J=6.6 Hz, 3H),1.2-1.4 (m, 20H), 1.46 (d, J=6.8 Hz, 1.5H), 1.52 (d, J=6.8 Hz, 1.5H),1.71 (m, 1H), 1.81 (m, 1H), 2.10 (s, 1.5H), 2.14 (s, 1.5H), 4.97 (dq,J=6.8 Hz, J=1.6 Hz, 0.5H), 5.11 (dq, J=6.8 Hz, J= 1.6 Hz, 0.5H), 5.52(brt, J=6.6 Hz, 0.5H), 5.57 (m, 0.5H), 5.89 (m, 0.5H), 5.47 (m, 0.5H).

¹³ C NMR (CDCl₃), mixture of diastereomers: 13.9, 18.3, 18.5, 20.6,22.5, 24.6, 24.9, 29.0, 29.1, 29.2, 29.3, 29.4, 31.7, 32.9, 33.4, 68.4,69.4, 78.3, 79.0, 115.3, 117.3, 169.6, 169.9, 170.6, 171.5, 171.6,171.7.

Elemental analysis: theoretical carbon 70.97%, found 71.09%. Theoreticalhydrogen 10.12%, found 10.32%.

4-Hydroxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 6)

LiOH (0.5M, 19.7 mL, 9.83 mmol) was added to a solution of4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5,see improved process for preparation below), in THF (20 mL) at roomtemperature. After stirring for 3 hours the reaction was quenched withglacial acetic acid (590 mg, 9.83 mmol) and the THF was removed byrotary evaporator. Solids were removed from the residual aqueous slurry.The clear aqueous solution containing the crude product was lyophylized,adhered to silica with methanol and purified by flash chromatographyusing 60% ethyl acetate/hexane to give the title alcohol.

IR (CHCl₃): 3300, 3023, 1766 cm⁻¹.

¹ H NMR (CDCl₃): 1.76 (s, 3H), 3.3 (vbrs, 1H), 4.57 (s, 2H), 5.7 (vbrs,1H), 7.32 to 7.42 (m, 5H).

¹³ C NMR (CDCl₃): 24.2, 56.2, 105.5, 128.3, 128.5, 129.1, 129.3, 158.3,170.5.

LRMS: m/x observed at 220 (M⁺).

4-Hydroxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 7)

To NaBH₄ (147 mg, 3.88 mmol) suspended in anhydrous ethylene glycoldimethyl ether (20 mL) at 0° C. under argon was added4-hydroxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 6) inethylene glycol dimethyl ether (20 mL) dropwise. After stirring for 3hours the solution was acidified to pH2 with 6N HCl, warmed to ambienttemperature and stirred an additional 1 hour. The solution wasconcentrated to 10 mL volume and the organics were extracted into ethylacetate. The combined organic fractions were washed with a saturatedsolution of aqueous sodium bicarbonate, H₂ O and brine. Evaporation ofthe dried (magnesium sulfate) extracts gave an oil which was purified byflash chromatography on silica using 30% ethyl acetate/hexane to givethe title compound.

IR (CHCl₃): 3616, 3300 (v. br.), 3022, 1747 cm⁻¹.

¹ H NMR (CDCl₃): 1.54 (d, J=6.8 Hz, 3H), 3.38 (m, 1H), 4.54 (dd, J=6.1Hz, J=14.9 Hz, 1H), 4.70 (dd, J=3.9 Hz, J=14.9 Hz, 1H), 5.24 (q, J=6.8Hz, 1H), 7.3-7.43 (m, 5H).

¹³ C NMR (CDCl₃): 18.3, 57.0, 78.2, 126.0, 128.4, 128.8 129.1, 164.6,172.9.

LRMS: m/z observed at 204 (M⁺).

4-Dodecoyloxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 4)

4-Hydroxymethyl-5-methyl-3-phenyl-2(5H)-furanone (Compound 7), (73 mg,0.36 mmol), lauroyl chloride (117 mg, 0.54 mmol), triethylamine (47 mg,0.47 mmol) and dimethylaminopyridine (1 mg, 0.01 mmol) were stirred inanhydrous THF (2 mL) at ambient temperature under argon for 2 hours. Thecrude reaction mixture was concentrated, the organics were extractedinto diethyl ether and solids were filtered off. The ether was removedby rotary evaporator and the resulting oil was purified by flashchromatography on silica to give the title compound.

IR (CHCl₃): 3027, 1751 cm⁻¹.

¹ H NMR (CDCl₃): 0.88 (t, J=6.6 Hz, 3H), 1.15 to 1.37 (m, 16H), 1.56 (d,J=6.7 Hz, 3H), 1.61 (m, 2H), 2.32 (m, 2H), 5.07 (d, J=4.4 Hz, 2H), 5.15(q, J=6.7 Hz, 1H), 7.36-7.49 (m, 5H).

¹³ C NMR (CDCl₃): 14.0, 18.4, 22.6, 24.7, 29.0, 29.1, 29.2, 29.3, 29.5,31.8, 33.8, 57.9, 77.4, 128.5, 128.8, 128.9, 129.1, 129.2, 157.6, 171.3,172.9.

Elemental analysis: theoretical carbon 74.58% found 74.58%; theoreticalhydrogen 8.87%, found 8.59%.

Improved Preparation of4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5)

    ______________________________________                                        Step 1. Preparation of 4-Phenyloxazole.                                                     Amount  MW      moles                                           ______________________________________                                        2-Bromoacetophenone                                                                            40 g     199.05  0.2                                         Ammonium Formate                                                                               44 g      63.06  0.7                                         Formic Acid     210 mL                                                        ______________________________________                                    

A mixture of 2-bromoacetophenone and ammonium formate in formic acid wasstirred at reflux under nitrogen for 2 hours. The cooled reactionmixture was treated with 400 mL of H₂ O and extracted with ether (3×200mL). The combined organics were washed with saturated aqueous NaHCO₃,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (eluting withEtOAc/hexanes, 1:9) to afford 8.9 g (31%) of 4-phenyloxazole as a yellowoil.

    ______________________________________                                        Step 2. Ethyl-4-phenylfuran-3-carboxylate.                                                 Amount   MW      moles                                           ______________________________________                                        4-Phenyloxazole                                                                              8.86 g     145     0.061                                       Ethyl phenylpropiolate                                                                       10.6 g     174.2   0.061                                       ______________________________________                                    

A mixture of 4-phenyloxazole and ethyl phenylpropiolate was heated at200°-210° C. in a sealed tube under N₂ for 22 hours. The cooled reactionmixture was purified by column chromatography (eluent, CH₂ Cl₂ /hexanes,1:1) to give 12.65 g (96%) of adduct as a red oil which was contaminatedwith phenylacetonitrile. Although the product obtained in thispreparation was not 100 % pure, it was used in the next step withoutfurther purification.

    ______________________________________                                        Step 3. (4-Phenyl-3-furyl)carbinol (Compound 10)                                         Amount      MW      moles                                          ______________________________________                                        ethyl-4-phenylfuran-3-                                                                     12.65     g       216   0.059                                    carboxylate                                                                   LiAlH.sub.4  1.23      g       37.95 0.033                                    THF          180 + 30  mL                                                     ______________________________________                                    

To the solution of ethyl-4-phenylfuran-3-carboxylate in dry THF (180 mL,freshly distilled from Na/benzophenone) was added dropwise thesuspension of lithium alumium hydride in THF (30 mL) at 0° C. undernitrogen. Then the mixture was warmed to room temperature and quenchedwith 1N HCl acid and extracted with EtOAc. The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (eluent, CH₂Cl₂) to afford 6.1 g (59%) of (4-phenyl-3-furyl)carbinol as whitecrystals.

    ______________________________________                                        Step 4. 4-Phenyl-3-furancarboxaldehyde (Compound 11)                                    Amount       MW      moles                                          ______________________________________                                        Compound 10 9.39       g       174   0.054                                    DMSO        8.44       g       78.13 0.108                                                (7.7       ml)                                                    TFAA        20.94      g       210.03                                                                              0.081                                                (28        ml)                                                    iPr.sub.2 NEt                                                                             20.94      g       129.25                                                                              0.162                                                (28        ml)                                                    CH.sub.2 Cl.sub.2                                                                         60 + 10 + 40                                                                             mL                                                     ______________________________________                                    

To a solution of DMSO (distilled from CaH₂) in dry CH₂ Cl₂ (60 mL,distilled from CaH₂) was added dropwise trifluoroacetic anhydride in dryCH₂ Cl₂ (10 mL) under nitrogen at -78° C. over approximately 15 minutes.The mixture was stirred at -78° C. for an additional 15 minutes. To theslurry was then added dropwise the starting material in dry CH₂ Cl₂ (40mL) at -78° C. over approximately 20 minutes. The yellow solution wasstirred at -78° C. for 1 hour. The iPr₂ NEt was then added at -78° C.and the solution was warmed gradually to room temperature. The reactionmixture was washed sequentially with 1N HCl and saturated aqueousNaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography(EtOAc/hexanes, 1:4) to give 8.88 g (96%) of4-phenyl-3-furancarboxaldehyde (Compound 11) as a yellow oil.

    ______________________________________                                        Step 5. 4-Phenyl-5-trimethylsilyl-3-                                          furancarboxaldehyde (Compound 12)                                                          Amount     MW      moles                                         ______________________________________                                        Compound 11    8.35     g       172   0.049                                   morpholine     4.44     g       87.12 0.051                                   n-BuLi, 2.5 M in hexanes                                                                     20.4     mL            0.051                                   s-Buli, 1.3 M in                                                                             44.8     mL            0.058                                   cyclohexane                                                                   TMSCl          7.91     g             108.64                                  THF            60 + 40  mL                                                    ______________________________________                                    

To the solution of morpholine (freshly distilled from CaH₂) in dry THF(60 mL) was added dropwise n-BuLi at 0° C. under nitrogen. The resultingsolution was stirred at 0° C. for an additional 15 minutes then cooledto -78° C., and aldehyde (Compound 11)in dry THF (40 mL) was addeddropwise. The mixture was warmed to 0° C. and stirred at 0° C. for 15minutes, then the mixture was recooled to -78° C., and the s-BuLi wasadded dropwise. The resulting slurry was stirred at -78° C. and thereaction mixture was gradually warmed to room temperature. The reactionmixture was quenched with saturated aqueous NH₄ Cl and extracted withEtOAc. The organic layer was dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (eluent, EtOAc/hexanes, 1:4) to give 8.08 g (68%) of4-phenyl-5-trimethylsilyl-3-furancarboxaldehyde (Compound 12) as ayellow oil.

    ______________________________________                                        Step 6.                                                                       (4-Phenyl-5-trimethylsilyl-3-furyl)carbinol (Compound 13)                                   Amount    MW     moles                                          ______________________________________                                        Compound 12     8.08    g       244  33                                       LiAlH.sub.4 (1.0 M in THF)                                                                    14.4    mL           12.4                                     THF             80      mL                                                    ______________________________________                                    

To the solution of trimethylsilyl-aldehyde (Compound 12) in dry THF wasadded dropwise the LiAlH₄ solution at 0° C. under nitrogen. The reactionmixture was stirred at 0° C. for 1 hour, then quenched with 1N HCl (60mL) and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (EtOAc/hexane, 1:4) togive 6.75 g (83%) of the title compound as a yellow oil.

    ______________________________________                                        Step 7. 5-Trimethylsilyl-4-                                                   phenyl-3-hydroxymethyl-2-methylfuran (Compound 14)                                         Amount   MW      moles                                           ______________________________________                                        Compound 13    6.8    g       246   0.028                                     n-BuLi, 2.5 M in hexanes                                                                     25     mL            0.063                                     LiCl           11.72  g       42.4  0.28                                      MeI            19.6   g       141.9 0.14                                      THF            120    mL                                                      ______________________________________                                    

To the solution of Compound 13 in dry THF was added dropwise n-BuLi at-78° C. under nitrogen. The reaction mixture was gradually warmed to-20° C., and the LiCl was added at -20° C., followed by MeI (freshlydistilled). The mixture was stirred at -20° C. for 24 hours, thenquenched with saturated aqueous NH₄ Cl, and extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(eluent, EtOAc/hexanes, 1:4) to give 6.37 g of product as a yellow oil.The product was contaminated with the 2-desmethyl compound (startingmaterial) but was suitable for the next reaction step. (Ratio of productto starting material, approximately 4:1 by proton NMR integration,corresponding to 71% yield of product).

    ______________________________________                                        Step 8. 5-trimethylsilyl-4-phenyl-3-                                          dodecoyloxymethyl-2-methylfuran (Compound 15)                                             Amount        MW      moles                                       ______________________________________                                        Compound 14   6.1    g        260    0.0235                                   lauroyl chloride                                                                            10.26  g        218.77                                                                              0.047                                     Triethylamine 4.75   g        101.19                                                                              0.047                                     THF           100    mL                                                       ______________________________________                                    

To the solution of Compound 14 in dry THF was added triethylamine at 0°C. under nitrogen, followed by lauroyl chloride. The mixture was stirredat 0° C. for 1 hour, then treated with water and extracted with ether.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (eluent, EtOAc/hexanes, 1:25) to give 12.14 g of productas a colorless oil in quantitative yield. This product was contaminatedwith its corresponding desmethyl analog.

    ______________________________________                                        Step 9. 4-dodecoyloxymethyl-5-hydroxy-                                        5-methyl-3-phenyl-2-furanone (Compound 5)                                                Amount        MW      moles                                        ______________________________________                                        Compound 15  13.66  g        442.27                                                                              31                                         Rose Bengal  50     mg             0.05                                       THF          1200   mL                                                        ______________________________________                                    

The solution of Compound 15 and Rose Bengal in THF was saturated withO₂, then cooled to approximately -5° C. (dry ice/acetone bath) andirradiated with a 150 watt flood lamp (maintaining the temperature ofthe mixture at -5° to 0° C.) for 3 hours. The reaction mixture was thenfiltered and concentrated to a pink oil which was purified by columnchromatography (eluent, EtOAc/hexanes, 1:20 to 1:4) to give 3.4 g (27%)of pure title compound as a colorless oil. An additional 3 g(approximately 25%) of a mixture of the title compound and the5-desmethyl derivative (ratio 1:1 by proton NMR integration) was alsoobtained as a yellow oil.

What is claimed is:
 1. A compound of the formula ##STR7## where R₁ isalkyl of 1 to 9 carbons; n is an integer having the values of 1 or 2,when n is 1 the R₁ group is attached to the 5 position of the2-furanone, when n is 2 then R₁ is attached to both the 3 and 5positions;Y₁ is H, alkyl of 1 to 20 carbons, phenyl C₁ -C₂₀ alkyl, C₁-C₂₀ alkenyl containing one or more olefinic bonds, PO(OH)₂, PO(OH)OR₂,PO(OH)R₂, PO(OR₂)₂, where R₂ is independently alkyl of 1 to 20 carbons,phenyl, halogen substituted phenyl or C₁ -C₆ alkyl substituted phenyl,further Y₁ is CO--R₃, CO--OR₃, CONHR₃, SO₂ R₃, SO₂ NHR₃, (CH₂)_(p)--O--R₃, or (CH₂)_(p) --O--(CH₂)_(m) --O--R₃, where p, and m, areintegers and are independently 1 to 20 and R₃ is H, C₁ -C₂₀ alkyl, C₁-C₂₀ alkenyl containing one or more olefinic bonds, phenyl, halogensubstituted phenyl or C₁ -C₆ alkyl substituted phenyl, with the provisothat when Y₁ is CO--OR₃ or CONHR₃ then R₃ is not hydrogen, and Y₂ is H,an alkyl group of 1 to 25 carbons, phenyl, naphthyl, phenyl (C₁-C₂₀)alkyl-, naphthyl (C₁ -C₂₀)alkyl-, halogen substituted phenyl, C₁-C₆ alkyl substituted phenyl, halogen substituted naphthyl, C₁ -C₆substituted naphthyl.
 2. A compound of claim 1 where R₁ is lower alkyl.3. A compound of claim 1 where n is
 1. 4. A compound of claim 1 where nis
 2. 5. A compound of claim 1 where Y₁ is H.
 6. A compound of theformula ##STR8## where R₁ independently is H, phenyl, C₁ -C₆ alkylsubstituted phenyl, halogen substituted phenyl, or alkyl of 1 to 9carbons;n is an integer having the values of 1 or 2, when n is 1 the R₁group is attached either to the 3 or to the 5 position of the2-furanone, when n is 2 then R₁ is attached to both the 3 and 5positions, with the proviso that the substituents in the 3 and 5positions both cannot be hydrogen; Y₂ is H, an alkyl group of 1 to 25carbons, phenyl, naphthyl, phenyl, (C₁ -C₂₀)alkyl-, napthyl, (C₁-C₂₀)alkyl-, halogen substituted phenyl, C₁ -C₆ alkyl substitutedphenyl, halogen substituted naphthyl, C₁ -C₆ substituted naphthyl.
 7. Acompound of claim 1 where Y₂ is H.
 8. A compound of claim 1 where Y₂ isalkyl having 4 to 25 carbons.
 9. A compound of claim 6 where Y₂ is H andR₃ is alkyl having 4 to 25 carbons.
 10. A compound of claim 6 where Y₂is alkyl having 4 to 25 carbons and R₃ is CH₃.
 11. A compound of theformula ##STR9## where R₁ is lower alkyl, n is an integer having thevalues of 1 or 2, when n is 1 the R₁ group is attached to the 5 positionof the 2-furanone, when n is 2 then R₁ is attached to both the 3 and 5positions;Y₁ is H or CH₃ CO, and Y₂ is an alkyl group of 8 to 16carbons.
 12. A compound of claim 11 where n is 1, and R₁ is 5-methyl.13. A compound of claim 12 where Y₂ is CH₃ (CH₂)₁₁.
 14. The compound ofthe formula ##STR10##
 15. The compound of claim 12 where Y₁ is H.
 16. Acompound of claim 11 where n is 1, and R₁ is 3-methyl.
 17. The compoundof the formula ##STR11## where Y₁ is H or CH₃ CO.
 18. The compound ofclaim 17 where Y₁ is CH₃ CO.
 19. A compound of the formula ##STR12##where R₁ independently is H, lower alkyl or phenyl, n is an integerhaving the values of 1 or 2, when n is 1 the R₁ group is attached eitherto the 3 or to the 5 position of the 2-furanone, when n is 2 then R₁ isattached to both the 3 and 5 positions, with the proviso that thesubstituents in the 3 and 5 positions both cannot be hydrogen;Y₁ is R₃CO where R₃ is alkyl of 4 to 25 carbons.
 20. A compound of claim 19where n is 2, one of the R₁ groups is methyl and the other is phenyl.21. A compound of claim 20 where the phenyl group is in the 3 positionand the methyl group is in the 5 position.
 22. The compound of claim 21where the R₃ group is CH₃ (CH₂)₁₁.